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1.
Arch Virol ; 2021 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-34762150

RESUMO

Negeviruses are a group of insect-specific viruses that have a wide geographic distribution and broad host range. In recent years, nege-like viruses have been discovered in aphids of various genera of the family Aphididae, including Aphis, Rhopalosiphum, Sitobion, and Indomegoura. Here, we report the complete genome sequence of a nege-like virus isolated from Astegopteryx formosana aphids collected in Guangdong, China, which we have designated as "Astegopteryx formosana nege-like virus" (AFNLV). AFNLV has a genome length of 10,107 nt (excluding the polyA tail) and possesses the typical conserved domains of negeviruses. These include a viral methyltransferase, an S-adenosylmethionine-dependent methyltransferase, a viral helicase, and an RNA-dependent RNA polymerase (RdRP) domain in open reading frame 1 (ORF1), a DiSB-ORF2_chro domain in ORF2, and a SP24 domain in ORF3. The genome of AFNLV shares the highest nucleotide sequence identity (74.89%) with Wuhan house centipede virus, identified in a mixture of barley aphids. As clearly revealed by RdRP-based phylogenetic analysis, AFNLV, together with other negeviruses and nege-like viruses discovered in aphids, formed a distinct "unclassified clade" closely related to members of the proposed genus "Sandewavirus" and the family Kitaviridae. In addition, small interfering RNAs (siRNAs) derived from AFNLV did not exhibit typical characteristics of virus-derived siRNAs processed by the host RNAi-based antiviral pathway. However, the extremely high abundance of viral transcripts (average read coverage 73,403X) strongly suggested that AFNLV might actively replicate in the aphid host. AFNLV described in this study is the first nege-like virus discovered in aphids of the genus Astegopteryx, which will contribute to future study of the co-evolution of nege/nege-like viruses and their host aphids.

2.
FASEB J ; 35(12): e22014, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34751973

RESUMO

Spinal cord injury (SCI) is a complex pathological change that includes primary SCI and gradually evolves into secondary SCI. Accumulating evidence demonstrates that circular RNAs (circRNAs) are involved in the pathology of a variety of neurological diseases and injuries. However, the characteristics and function of circRNAs in SCI have yet to be elucidated. Although previous research demonstrated that circPrkcsh induces astrocytes to produce inflammatory factors and chemokines, the precise function and mechanism of circPrkcsh in microglia after SCI remains unknown. In this study, we constructed a mouse model of SCI by applying a SCI impactor. Quantitative Real-time PCR and Fluorescence in situ hybridization analysis revealed that circPrkcsh was upregulated in the microglia of SCI mice when compared to sham-operated mice. Gain- or loss-of-function experiments and in vivo assays further indicated that circPrkcsh promotes microglia M1 polarization both in vivo and in vitro. Furthermore, bioinformatics analysis, dual-luciferase assays, and RNA immunoprecipitation assays, confirmed that circPrkcsh serves as a competing endogenous RNA (ceRNA) to promote the expression of MEKK1 mRNA by sponging miR-488. Double knockout rescue experiments further showed that circPrkcsh regulates the MEKK1/JNK/p38 MAPK pathway via miR-488. Our research provides a better understanding of the mechanism of circPrkcsh in SCI and demonstrates that the circPrkcsh/miR-488/Mekk1 axis is a promising regulatory method for the treatment of SCI.

3.
Neuroimage ; 244: 118588, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34607021

RESUMO

Recent resting-state fMRI studies have shown that brain activity exhibits temporal variations in functional connectivity by using various approaches including sliding window correlation, co-activation patterns, independent component analysis, quasi-periodic patterns, and hidden Markov models. These methods often model the brain activity as a discretized hopping among several brain states that are defined by the spatial configurations of network activity. However, the discretized states are merely a simplification of what is likely to be a continuous process, where each network evolves over time following its unique path. To model these characteristic spatiotemporal trajectories, we trained a variational autoencoder using rs-fMRI data and evaluated the spatiotemporal features of the latent variables obtained from the trained networks. Our results suggest that there are a relatively small number of approximately orthogonal whole-brain spatiotemporal patterns that capture the most prominent features of rs-fMRI data, which can serve as the building blocks to construct all possible spatiotemporal dynamics in resting state fMRI. These spatiotemporal patterns provide insight into how activity flows across the brain in concordance with known network structures and functional connectivity gradients.

4.
Adv Mater ; : e2106317, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34655105

RESUMO

Electromechanical interaction of cells and extracellular matrix are ubiquitous in biological systems. Understanding the fundamentals of this interaction and feedback is critical to design next-generation electroactive tissue engineering scaffold. Herein, based on elaborately modulating the dynamic mechanical forces in cell microenvironment, the design of a smart piezoelectric scaffold with suitable stiffness analogous to that of collagen for on-demand electrical stimulation is reported. Specifically, it generated a piezoelectric potential, namely a piezopotential, to stimulate stem cell differentiation with cell traction as a loop feedback signal, thereby avoiding the unfavorable effect of early electrical stimulation on cell spreading and adhesion. This is the first time to adapt to the dynamic microenvironment of cells and meet the electrical stimulation of cells in different states by a constant scaffold, diminishing the cumbersomeness of inducing material transformation or trigging by an external stimulus. This in situ on-demand electrical stimulation based on cell-traction-mediated piezopotential paves the way for smart scaffolds design and future bioelectronic therapies.

5.
Cancer Med ; 10(22): 8079-8090, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34647688

RESUMO

Metastatic upper urinary tract urothelial carcinoma (mUTUC) is a relatively rare urothelial carcinoma, and little attention has been given to it. Our study established a nomogram by analyzing the prognostic factors of mUTUC to predict the survival of patients and revealed that the role of surgery at the primary tumor site. We extracted our data (2010-2016) from the Surveillance, Epidemiology, and End Results (SEER) database, and 628 patients with distant metastasis were identified. Propensity score matching (PSM) was used to balance the clinical variable bias in a 1:1 ratio. After PSM, we enrolled 502 patients in our study cohort. Univariate and multivariate Cox regression analyses and Kaplan-Meier curves showed that T stage, N stage, hepatic metastasis, surgery, and chemotherapy were prognostic factors for mUTUC before and after PSM. Based on the findings, a nomogram was constructed to predict the 12-month survival of patients with distant metastasis. The analysis of subgroups of T stage, N stage, and different metastatic sites demonstrated that the survival of patients with T1/T2, N0/N1/N2/N3, metastasis including liver, and metastasis including bone could be improved by a combination of surgery and chemotherapy, while for the patients with T3/T4/TX, NX, metastasis including lung, and metastasis including distant lymph nodes, chemotherapy alone was a better choice to improve their overall survival. Radiotherapy has been proven to be useful for patients with N1/N2/N3 stage. We have provided more precise treatment strategies for stage IV patients. Our research fully affirms the role of surgery on primary site in UTUC patients with distant metastasis and the significance of classifying the patients into subgroups by integrating variables including T stage, N stage, and different metastatic sites to select the optimal treatment method.

6.
Int J Biol Sci ; 17(11): 2795-2810, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34345208

RESUMO

Reactive astrocytes are implicated in traumatic spinal cord injury (TSCI). Interestingly, naïve astrocytes can easily transform into neurotoxic reactive astrocytes (A1s) with inflammatory stimulation. Previous studies demonstrated that microRNA(miR)-21a-5p was up-regulated in spinal cord tissue after TSCI; however, it is not clear whether this affected reactive astrocyte polarization. Here, we aim to detect the effects of miR-21a-5p on the induction of A1 formation and the underlying mechanisms. Our study found that the expression of miR-21a-5p was significantly increased while that of Cntfr α was decreased, since naïve astrocytes transformed into A1s 3 days post-TSCI; the binding site between miR-21a-5p and Cntfr α was further confirmed in astrocytes. After treatment with CNTF, the levels of A1 markers decreased while that of A2 increased. The expression of A1 markers significantly decreased with the downregulation of miR-21a-5p, while Cntfr α siRNA treatment caused the opposite both in vitro and in vivo. To summarize, miR-21a-5p/Cntfr α promotes A1 induction and might enhance the inflammatory process of TSCI; furthermore, we identified, for the first time, the effect and potential mechanism by which CNTF inhibits naïve astrocytes transformation into A1s. Collectively, our findings demonstrate that targeting miR-21a-5p represents a prospective therapy for promoting the recovery of TSCI.

7.
Foods ; 10(8)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34441718

RESUMO

The development of an efficient pretreatment, prior to enzymatic hydrolysis, is a good strategy for the sustainable use of refractory fish byproducts. This study compared hydrothermal pretreatments at 159 °C for 2 min, followed by water extraction (steam explosion-assisted extraction, SE) and 121 °C for 70 min (hot-pressure extraction, HPE), for the recovery of proteins from fish backbones. The effect of enzymatic hydrolysis on the properties of the obtained fish bone protein (FBP) was also evaluated. The results demonstrated that FBP had high contents of protein (81.09-84.88 g/100 g) and hydroxyproline (70-82 residues/1000 residues). After hydrolysis with Flavourzyme, for 3 h, the FBP hydrolysates that were pretreated with SE (SFBP-H) exhibited a better degree of hydrolysis (DH) and nitrogen recovery (NR), and a higher level of umami taste free amino acids (151.50 mg/100 mL), compared with the HPE-treated samples. The obtained SFBP-H mainly distributed below 3000 Da and had strong scavenging effects on 1,1-diphenyl-2-picrylhydrazy (DPPH) (IC50 = 4.24 mg/mL) and 2,2-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) (IC50 = 1.93 mg/mL) radicals. Steam explosion-assisted extraction is a promising route for recovering proteins from native fish bone materials, and improving the flavor and antioxidant activity of the hydrolysates.

8.
Front Oncol ; 11: 681261, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34178669

RESUMO

Microliposome maintenance (MCM) 2, MCM3, MCM4, MCM5, MCM6, and MCM7 are DNA replication regulators and are involved in the progression of multiple cancer types, but their role in ovarian cancer is still unclear. The purpose of this study is to clarify the biological function and prognostic value of the MCM complex in ovarian cancer (OS) progression. We analyzed DNA alterations, mRNA and protein levels, protein structure, PPI network, functional enrichment, and prognostic value in OC based on the Oncomine, cBioPortal, TCGA, CPTAC, PDB, GeneMANIA, DAVID, KEGG, and GSCALite databases. The results indicated that the protein levels of these DNA replication regulators were increased significantly. Moreover, survival analysis showed a prognostic signature based on the MCM complex, which performed moderately well in terms of OS prognostic prediction. Additionally, protein structure, functional enrichment, and PPI network analyses indicated that the MCM complex synergistically promoted OC progression by accelerating DNA replication and the cell cycle. In conclusion, our study suggested that the MCM complex might be a potential target and prognostic marker for OC patients.

9.
Surgery ; 170(3): 664-672, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34090677

RESUMO

BACKGROUND: Surgical indications for the treatment of gallbladder polyps are controversial. Evaluation of gallbladder polyps with malignant tendency and indications for cholecystectomy in patients with long diameter polyps of 10 to 15 mm require further analysis and discussion. In this study, our objective was to re-evaluate indications for the surgical resection of gallbladder polyps and construct a nomogram model for the prediction of gallbladder polyps with malignant tendency. METHODS: Clinicopathologic data of 2,272 patients who had undergone cholecystectomy for gallbladder polyps were collected from 11 medical centers in China. Risk factor analyses and nomogram prediction model for gallbladder polyps with malignant tendency were conducted. RESULTS: Excluding 311 patients with cholelithiasis and 488 patients with long diameter polyps ≤5 and >15 mm, factors that differed significantly among patients with gallbladder polyps having a long diameter of 6 to 9 mm (885 cases) and 10 to 15 mm (588 cases) were polyp detection time, CEA and CA19-9 levels, number of polyps, fundus, echogenicity, gallbladder wall thickness and postoperative pathologic features (P < .05). Among 588 patients with gallbladder polyps with a long diameter of 10 of 15 mm, multivariate analysis indicated the following independent risk factors of gallbladder polyps with malignant tendency: single polyps (OR = 0.286/P < .001), polyps with broad base (OR = 2.644/P = .001), polyps with medium/low echogenicity (OR = 2.387/P = .003), and polyps with short diameter of 7 to 9 or 10 to 15 mm (OR = 3.820/P = .005; OR = 2.220/P = .048, respectively). The C-index of the nomogram model and internal validation were .778 and .768, respectively. In addition, a sample online calculator for the nomogram prediction model had been created (https://docliqi.shinyapps.io/dynnom/). CONCLUSION: Indications for cholecystectomy in patients with gallbladder polyps with a long diameter of 10 to 15 mm should be assessed by combining the information on short diameter, number of polyps, fundus, and echogenicity. The nomogram model can be used to predict the risk for the development of gallbladder polyps with malignant tendency.


Assuntos
Colecistectomia Laparoscópica/métodos , Neoplasias da Vesícula Biliar/diagnóstico , Estadiamento de Neoplasias/normas , Nomogramas , Pólipos/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , China/epidemiologia , Progressão da Doença , Feminino , Seguimentos , Neoplasias da Vesícula Biliar/epidemiologia , Neoplasias da Vesícula Biliar/cirurgia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Pólipos/cirurgia , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
10.
Front Cell Neurosci ; 15: 673439, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34177467

RESUMO

The development and stabilization of neuronal circuits are critical to proper brain function. Synapses are the building blocks of neural circuits. Here we examine the effects of the neuropeptide oxytocin on synaptic transmission in L2/3 pyramidal neurons of the barrel field of the primary somatosensory cortex (S1BF). We find that perfusion of oxytocin onto acute brain slices significantly increases the frequency of miniature excitatory postsynaptic currents (mEPSC) of S1BF L2/3 pyramidal neurons at P10 and P14, but reduces it at the later ages of P22 and P28; the transition occurs at around P18. Since oxytocin expression is itself regulated by sensory experience, we also examine whether the effects of oxytocin on excitatory synaptic transmission correlate with that of sensory experience. We find that, indeed, the effects of sensory experience and oxytocin on excitatory synaptic transmission of L2/3 pyramidal neurons both peak at around P14 and plateau around P18, suggesting that they regulate a specific form of synaptic plasticity in L2/3 pyramidal neurons, with a sensitive/critical period ending around P18. Consistently, oxytocin receptor (Oxtr) expression in glutamatergic neurons of the upper layers of the cerebral cortex peaks around P14. By P28, however, Oxtr expression becomes more prominent in GABAergic neurons, especially somatostatin (SST) neurons. At P28, oxytocin perfusion increases inhibitory synaptic transmission and reduces excitatory synaptic transmission, effects that result in a net reduction of neuronal excitation, in contrast to increased excitation at P14. Using oxytocin knockout mice and Oxtr conditional knockout mice, we show that loss-of-function of oxytocin affects baseline excitatory synaptic transmission, while Oxtr is required for oxytocin-induced changes in excitatory synaptic transmission, at both P14 and P28. Together, these results demonstrate that oxytocin has complex and dynamic functions in regulating synaptic transmission in cortical L2/3 pyramidal neurons. These findings add to existing knowledge of the function of oxytocin in regulating neural circuit development and plasticity.

11.
Biomed Pharmacother ; 140: 111775, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34062413

RESUMO

Combination therapies with chemotherapy and traditional Chinese medicines are attracted increasing attentions for cancer treatment in China. Shengbai decoction (SBD) is a traditional Chinese compound medicine, composed of 6 traditional Chinese herbs. The aim of this study was to investigate the synergistic anti-tumor activity of SBD with cyclophosphamide (CTX) and the possibly underlying mechanisms in treating the hepatoma 22 (H22) -bearing mice. The liver cancer models in C57BL/6 mice were established by injecting with mouse H22 cancer cells. Results showed that combination treatment with SBD and CTX processed a significantly synergistic anti-tumor effect in H22 tumor-bearing mice. Moreover, SBD could not only improve leukopenia caused by CTX, but prolong the survival time of the mice. Furthermore, SBD could upregulate the expressions of the pro-apoptotic genes, including p53, BAD, Cas3 and Bax, and suppress the expression of anti-apoptotic gene Bcl-2. These results suggested that the combination treatment with SBD and CTX had health improving function and less side effects compared with the administration of CTX alone, and SBD could be a promising adjunct agent for liver cancer chemotherapy.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Medicamentos de Ervas Chinesas/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Contagem de Células Sanguíneas , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Citocinas/sangue , Medicamentos de Ervas Chinesas/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos C57BL
12.
Cancer Chemother Pharmacol ; 88(3): 465-474, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34086067

RESUMO

PURPOSE: To compare the pharmacokinetic profiles, safety and immunogenicity of proposed bevacizumab biosimilar HLX04 with reference bevacizumab in healthy Chinese males. METHODS: In this double-blind Phase 1 study, healthy volunteers (N = 208) were randomized 1:1:1:1 to a single 3 mg/kg intravenous infusion of HLX04 or reference bevacizumab sourced from the United States (bevacizumab-US), the European Union (bevacizumab-EU) or China (bevacizumab-CN). Co-primary endpoints were area under the serum concentration-time profile (AUC) from time zero extrapolated to infinity (AUC0-inf) and from zero to last quantifiable concentration (AUClast). Secondary endpoint was the maximum serum drug concentration (Cmax). Study participants were monitored for treatment-emergent adverse events (TEAEs) and samples were collected for anti-drug antibody (ADA) testing throughout the study. RESULTS: Pharmacokinetic parameters were similar across groups. The respective geometric least-squares mean ratios (GLSMR) of AUC0-inf, AUClast and Cmax were: 95.7%, 96.0% and 101.8% for HLX04 versus bevacizumab-US; 94.3%, 94.6% and 100.5% for HLX04 versus bevacizumab-EU; and 90.0%, 90.4% and 98.2% for HLX04 versus bevacizumab-CN. For all test-to-reference comparisons, two-sided 90% confidence intervals of GLSMR for AUC0-inf, AUClast and Cmax fell in the pre-specified bioequivalence range (80-125%). There were no notable differences in the frequency, nature and/or grade of TEAEs. No deaths were reported and no ADAs were detected during the study. CONCLUSION: HLX04 had similar safety and pharmacokinetic profiles to reference bevacizumab in healthy Chinese males, supporting the confirmatory Phase 3 study investigating the efficacy and safety equivalence between HLX04 and bevacizumab in patients with metastatic colorectal cancer (NCT03511963). CLINICAL TRIAL REGISTRATION: The study was registered with Clinicaltrials.gov, NCT03483649.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Bevacizumab/administração & dosagem , Medicamentos Biossimilares/administração & dosagem , Adulto , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacocinética , Área Sob a Curva , Bevacizumab/efeitos adversos , Medicamentos Biossimilares/efeitos adversos , Medicamentos Biossimilares/farmacocinética , China , Método Duplo-Cego , União Europeia , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Equivalência Terapêutica , Estados Unidos , Adulto Jovem
13.
NPJ Biofilms Microbiomes ; 7(1): 43, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33986295

RESUMO

A large number of insect-specific viruses (ISVs) have recently been discovered, mostly from hematophagous insect vectors because of their medical importance, but little attention has been paid to important plant virus vectors such as the whitefly Bemisia tabaci, which exists as a complex of cryptic species. Public SRA datasets of B. tabaci and newly generated transcriptomes of three Chinese populations are here comprehensively investigated to characterize the whitefly viromes of different cryptic species. Twenty novel ISVs were confidently identified, mostly associated with a particular cryptic species while different cryptic species harbored one or more core ISVs. Microinjection experiments showed that some ISVs might cross-infect between the two invasive whitefly cryptic species, Middle East Asia Minor 1 (MEAM1) and Mediterranean (MED), but others appeared to have a more restricted host range, reflecting the possibility of distinct long-term coevolution of these ISVs and whitefly hosts. Moreover, analysis of the profiles of virus-derived small-interfering RNAs indicated that some of the ISVs can successfully replicate in whitefly and the antiviral RNAi pathway of B. tabaci is actively involved in response to ISV infections. Our study provides a comprehensive analysis of the RNA virome, the distinct relationships and cross-cryptic species infectivity of ISVs in an agriculturally important insect vector.


Assuntos
Hemípteros/virologia , Vírus de RNA/classificação , Vírus de RNA/genética , Viroma , Animais , Bases de Dados Genéticas , Especificidade de Hospedeiro , Insetos Vetores/virologia , Metagenoma , Metagenômica/métodos , Filogenia , RNA Viral
14.
Sci Total Environ ; 776: 145965, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33647659

RESUMO

Iron (Fe) is a micronutrient and plays an important role in regulating ocean primary production and consequently changing oceanic CO2 uptake. However, approaches for high-resolution of Fe records in marine environment has been a great challenge. In this study, we report for the first time an annual Fe record on black coral organic skeleton from the northern South China Sea (SCS) as an archive to study the environmental change during the past century. In situ micro-Raman, synchrotron micro X-ray absorption near edge spectroscopy (µ-XANES) and synchrotron micro X-ray fluorescence (µ-XRF) were applied to investigate the Fe speciation and the radial Fe profile in black coral. The preliminary results from micro-Raman and synchrotron micro XANES analysis demonstrated that Fe in black coral was mainly combined with 3,4-dihydroxyphenylalanine (dopa) as tris-DOPA-Fe complex. Such spatial coordination structure of complexation makes Fe have high affinity with dopa in black coral. Furthermore, elevated Fe concentration in Fe profile recorded on synchrotron µ-XRF spectra with 2.5 µm resolution corresponded well to the exploitation history of the adjacent onshore Tiandu Iron Mine (Sanya, China) from 1939 to 1960. Other distinct Fe peak coincides with the war activities in 1970s. The findings presented in this work indicate that the high-resolution iron record with low annual growth rate (~17.8 µm year-1) of black coral may serve as a proxy of marine environmental record.


Assuntos
Antozoários , Ferro , Animais , China , Mineração , Oceanos e Mares , Espectroscopia por Absorção de Raios X
15.
Pharmacol Res Perspect ; 9(2): e00733, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33682358

RESUMO

The primary objective of this randomized, double-blind, parallel-controlled study (from December 2016 to October 2018) was to evaluate pharmacokinetic (PK) equivalence of adalimumab biosimilar HLX03 and reference adalimumab in healthy volunteers, and to assess safety, and immunogenicity of HLX03. The primary PK endpoints were maximum observed plasma concentration (Cmax ) and area under the concentration curve from time zero to the last quantifiable concentration (AUC0-t ). Equivalence was determined if the 90% confidence interval (CI) of geometric least square mean ratio between the two treatment groups were within the predefined range of 80%-125%. Safety and immunogenicity were monitored during the study. Healthy Chinese males (N = 220) were randomized 1:1 to receive a single subcutaneous 40 mg dose of HLX03 or China (CN)-sourced adalimumab. The ratios of the geometric mean of Cmax and AUC0-t were 102.2% and 105.7%, respectively, with corresponding 90% CIs falling in the predefined margins, which demonstrated PK equivalence between HLX03 and CN-adalimumab. The incidence of treatment-emergent adverse events (TEAEs) was similar in the two groups (73.8% and 66.0% in the HLX03 and CN-adalimumab groups, respectively). Grade 3-4 TEAEs were reported in 7.5% and 5.7% of participants, respectively. The incidences of participants with antidrug antibodies (HLX03: 96.2%; CN-adalimumab: 93.4%) or neutralizing antibodies (HLX03: 40.6%, CN-adalimumab: 41.4%) were comparable between groups. This study demonstrated PK bioequivalence between HLX03 and CN-adalimumab, with similar safety and immunogenicity profiles. These data support further clinical development of HLX03 as an adalimumab biosimilar.

16.
Food Chem ; 354: 129565, 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-33756323

RESUMO

Polyunsaturated phospholipids are abundant in clam (Corbicula fluminea) but difficult to be fully extracted. Herein, graphene/fibrous silica (G/KCC-1) nanohybrids were synthesized, characterized, and applied for solid-phase extraction (SPE) of phospholipids in clam. The effectiveness of G/KCC-1 SPE was verified by hydrophilic interaction chromatography mass spectrometry (HILIC-MS) based lipidomics and statistical analysis. The ions of PE 16:0/18:1 (m/z 716.4), PC 16:0/20:5 (m/z 824.6) and etc. were regarded as the main difference among the crude lipids, acetone washed extract, and eluate of G/KCC-1 SPE. Finally, this method was validated in terms of linearity (R2 0.9965 to 0.9981), sensitivity (LOD 0.19-0.51 µg·mL-1 and LOQ 0.48 - 1.47 µg·mL-1), and precision (RSDintra-day ≤ 7.16% and RSDinter-day ≤ 7.30%). In conclusion, the G/KCC-1 SPE and HILIC-MS method was shown to be accurate and efficient in selective extracting and phenotyping phospholipids in C. fluminea.


Assuntos
Cromatografia Líquida , Corbicula/metabolismo , Grafite/química , Lipidômica/métodos , Espectrometria de Massas , Dióxido de Silício/química , Extração em Fase Sólida , Animais , Interações Hidrofóbicas e Hidrofílicas , Fenótipo , Alimentos Marinhos/análise
17.
Invest New Drugs ; 39(5): 1315-1323, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33713216

RESUMO

Purpose This study aimed to evaluate the safety and pharmacokinetic (PK) profiles of HLX07, a novel, recombinant, humanized anti-epidermal growth factor receptor (EGFR) antibody, in patients with advanced solid cancers who had failed standard therapy or for whom no standard therapy was available. Methods In this prospective, open-label, Phase I dose escalation study, patients aged ≥18 years (≥20 years for patients in Taiwan) with histologically-confirmed metastatic or recurrent epithelial carcinoma that had no K-RAS or B-RAF mutations were enrolled in a '3 + 3' escalation design. HLX07 was administered weekly by 2-h intravenous infusion at doses ranging from 50 to 800 mg. The primary endpoint was summary listing of participants reporting treatment-emergent adverse events (TEAEs). Secondary endpoints included PK analysis, serum anti-HLX07 antibody assessments and efficacy. Results In total, 19 patients were enrolled between 1 October 2016 and 16 July 2019 to receive HLX07 at doses of 50 (n = 3), 100 (n = 3), 200 (n = 3), 400 (n = 3), 600 (n = 3) and 800 (n = 4) mg per week. All patients experienced at least one TEAE, most commonly fatigue (68.4%), nausea (47.4%), paronychia (31.6%) and vomiting (31.6%). Serious TEAEs were reported in 11 patients but only one serious TEAE (dyspnea in 600 mg cohort) was regarded as possibly related to study treatment. No dose limiting toxicity (DLT) was reported. Systemic exposure to HLX07 increased proportionally with dose. Anti-HLX07 antibodies were not detected in any patients. Conclusion HLX07 was well tolerated (at dose levels up to 800 mg/week) and promising in patients with advanced solid cancers.Clinical Trial Registration: The study was registered at ClinicalTrials.gov : NCT02648490 (Jan 7, 2016).

18.
Front Pharmacol ; 12: 609992, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33776762

RESUMO

Sini Decoction (SND), as a classic prescription of Traditional Chinese Medicine (TCM), has been proved to be clinically useful in cardiomyopathy and inflammatory bowel diseases. However, the role and mechanism of SND in colitis-associated cancer remains unclear. This study aims to evaluate the effect of SND on colorectal cancer(CRC) symptoms and further explore the changes of gut microbes mediated by SND extract in azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CRC mice through 16 S rRNA sequencing. Our results indicated that treatment with SND extract could ameliorate the tumors' malignant degree by decreasing tumor number and size. Also, the expression levels of Cyclooxygenase 2 and Mucin-2, which are typical CRC biomarkers, were reduced compared to the CRC group. In the meantime, SND extract can upregulate CD8+ T lymphocytes' expression and Occludin in the colonic mucosal layer. Besides, SND inhibited the expression of CD4+ T cells and inflammatory cytokines in CRC tissue. According to bioinformatics analysis, SND extract was also suggested could modulate the gut microbial community. After the SND treatment, compared with the CRC mice model, the number of pathogenic bacteria showed a significant reduction, including Bacteroides fragilis and Sulphate-reducing bacteria; and SND increased the relative contents of the beneficial bacteria, including Lactobacillus, Bacillus coagulans, Akkermansia muciniphila, and Bifidobacterium. In summary, SND can effectively intervene in colorectal cancer development by regulating intestinal immunity, protecting the colonic mucosal barrier, and SND can change the intestinal microbiota composition in mice.

19.
Am J Cancer Res ; 11(2): 546-560, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33575086

RESUMO

Patients with epidermal growth factor receptor (EGFR) mutations in lung adenocarcinoma can benefit from targeted therapy. However, noninvasively determination of EGFR mutation status before targeted therapy remains a challenge. This study constructed a nomogram based on a combination of radiomics features with the clinical and radiological features to predict the EGFR mutation status. The least absolute shrinkage and selection operator (LASSO) and Wilcoxon test were used for feature selection. Decision tree (DT), logistic regression (LR), and support vector machine (SVM) classifiers were used for radiomics model building. Used the clinical and radiological features establish clinical-radiology (C-R) model. The C-R model with the best radiomics model to establish clinical-radiological-radiomics (C-R-R) model. The predictive performance of the model was evaluated by ROC and calibration curves, and the clinical usefulness was assessed by a decision curve analysis. The current study showed that twelve radiomics features were significantly associated with EGFR mutations. The best radiomics signature model was obtained using the SVM classifier. The C-R-R model had the best distinguishing ability for predicting the EGFR mutation status, with an AUC of 0.849 (95% CI, 0.805-0.893) and 0.835 (95% CI, 0.761-0.909) in the development and validation cohorts, respectively. Our study provides a non-invasive C-R-R model that combines CT-based radiomics features with clinical and radiological features, which can provide useful image-based biological information for targeted therapy candidates.

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